Jordan Axelrad, MD, MPH

Hello, and thank you for joining this MEDcast series titled “

Concurrent Management of Inflammatory Bowel Disease and Psoriatic Arthritis

.” I am Dr David Hudesman, co-director at the Inflammatory Bowel Disease Center at NYU Langone Health in New York.

I’m Dr Jordan Axelrad, director of Clinical and Translational Research at the Inflammatory Bowel Disease Center at NYU Langone Health in New York.

In this program we’ll discuss strategies for managing coexisting inflammatory bowel disease [IBD] and psoriatic arthritis, and the importance of a multidisciplinary approach to providing comprehensive care. To discuss more of this, we are joined by Dr Jose Scher, Steere-Abramson Associate Professor of medicine and rheumatology at the NYU Grossman School of Medicine, New York. Thank you so much for joining us. Let’s begin.

Jordan, just to kick off this discussion, talk about extraintestinal manifestations [EIMs] in inflammatory bowel disease? How often are we seeing this? What are the most common types?

Sure. Extraintestinal manifestations are disease findings that are external to the GI [gastrointestinal] tract in patients with inflammatory bowel disease. In some studies, these are incredibly common. Up to 40% or 50% of patients may have an extraintestinal manifestation of their IBD, inflammatory bowel disease. These commonly involve skin, joints, liver, kidney, eyes, really any organ outside of the GI tract. Skin and joints tend to be the most common, which hopefully we’re going to get into today, but these can be incredibly difficult to manage and may require expert consultation with colleagues in rheumatology or dermatology.

We’re happy to have our expert here, Jose. Jose, on the flip side, in your rheumatology clinic, how often are you seeing GI symptoms or something that concerns you that there might be something underlying, some type of subclinical bowel inflammation or IBD in your rheumatology patients, specifically psoriasis and psoriatic arthritis?

Thank you both for the invitation. It’s a pleasure to be here. I’d say it’s fairly common if you take the entire spectrum of manifestation. By that I mean, in general, we would see somewhere in the order of 5% of our patients with psoriatic disease and/or axial spondyloarthritis having clinically overt IBD or concomitant IBD. The intriguing part of it is that depending on the studies up to half of our patients have a form of subclinical, meaning not clinically evident gut inflammation, which may or may not manifest itself over time.

I think such high rates on both ends of the spectrum that the collaboration is extremely important. For us, we see some of that data as well, as Jordan was alluding to, especially when we’re looking at arthralgias and spondyloarthropathies, rates as low as 10% to upwards of 50%. So when you’re seeing a patient like that in your office, what’s the usual workflow when you’re concerned about any subclinical GI inflammation? Are you sending anything into your office? Are you referring to us right away?

I call you guys up quickly. We do a physical exam. We take the history that we know how to take. We’re not super comprehensive as you all are. You guys have scores that you go through and screening methodology more specifically. We do a little bit of protecting, an ASCA [anti-Saccharomyces cerevisiae antibodies] type approach or looking at biomarkers to discern whether or not there’s something that merits a quicker referral. We certainly ask about the usual questions of bowel movement frequency, hematochezia, abdominal pain, etc. And so, obviously, we have this ongoing and smooth collaboration between our centers that is very helpful to us as clinicians, but most importantly to our patients because we have this ongoing dialogue that’s helpful for clinical care.

Jordan, how do you ask about extraintestinal manifestations when you’re seeing somebody in the office? Because I think we all, including myself, don’t do as good of a job as we should.

I think that it’s probably underappreciated in the GI office. The actual magnitude of extraintestinal manifestations, in particular, the joint and skin manifestations of IBD are really underappreciated and I think we’re learning the right way to ask that. I learned from Jose that I should be asking about back pain, which I now ask specifically about in addition to just joint pain because you want to know about spondyloarthropathy and axial involvement and whatnot. That also influences how we think about the right medications and also the right types of doctors that they also need to see to be on the same treatment team as far as dermatology or rheumatology. Back pain has come into joint pain, and then, of course, I go into things like vision, skin, rash. Those are really the big ones.

I think that’s a great point. When we ask, when I first started, I would just say, do you have joint pains? Yes or no? Then they say, “No,” and then they’ll just bring it up later. I think we need to do a better job of asking these questions in the office because, as you just alluded to, it’s really going to affect our treatment decisions now that we have more therapeutic options, some that are more targeted, which might be good for 1 reason but maybe not as good for patients with extraintestinal manifestations.

Jose, let’s say I have a patient I asked about joint pains that said their knee hurts or their back hurts. What other questions should we be asking as gastroenterologists that could help us determine if this is something to call our rheumatologist about? Should we send other tests, or is it somebody that’s just ran a few miles or they’re getting older and it’s just a little wear and tear?

Really good question, Dave. Patients with diabetes, and similarly to those with spondyloarthritis or psoriatic arthritis, tend to be on the young side. Obviously, young is a relative term, at least for me it is. But we’re talking about patients in their 20s, 30s, and 40s and therefore you eliminate right away the wear and tear type of joint pain, osteoarthritis, and the like. You really want to focus on whether or not this pain is secondary to trauma or exercising. A lot of people, particularly in New York where we practice, are runners or do high-impact sports. You really want to know whether that’s a meniscal tear or if they’ve been having some other trauma or microtrauma that would explain that particular joint pain.

What we’re interested in are symptoms of pain in a specific joint that associate with swelling, for example. Swelling is a huge one. If you have swelling and pain, that’s more likely to be inflammatory in nature unless there was trauma to begin with. Redness and warmth are other signs leading towards a differential diagnosis of inflammatory disease. The third one could be a history of infection. Again, the Northeast and Lyme disease go together. So that’s a good question to ask. Have you been bitten by one of these bugs at all? Or any other infections, Caribbean-related trips where you have the viral syndromes like chikungunya, Zika virus, etc.? Beyond that, I think we want to make sure that there’s a screening process where not every joint pain equals inflammatory arthritis.

Jose, what do you think about the patients that come in and say, they wake up in terrible back pain or terrible joint pain and then throughout the day it starts to get better? Is that good enough to help differentiate between inflammatory and noninflammatory?

I would say yes, for the most part. Just for the record, what I was referring to before was peripheral arthritis … etc. Embedded in your question is, is this a lower back pain that’s inflammatory in nature? We indeed classify those as back pain that starts in the morning, typically in someone who is 40 years of age or younger that associates with morning stiffness of an hour or more. As you pointed out, typically it gets better or improves with mobility or exercise. Unlike, and the huge differentiating factor, is if you had a slipped disc or you had some sort of radiculopathy, where that pain is there constantly. No matter what you do, if you have a herniated disc you will not get any improvement with mobility. Actually, you may worsen that pain because the slipped disc will be in contact with the nerves that are being impacted by the slipped disc. So yes, those questions are very important.

The fifth point on discerning inflammatory back pain from noninflammatory back pain has come up recently, and that is the use of NSAIDs [non-steroidal anti-inflammatory drugs]. If a patient says that with NSAIDs they get better, then that’s more likely to be related to an inflammatory process. The challenge there is that the new data doesn’t necessarily show that. That improvement with NSAIDs is true for both inflammatory and noninflammatory pain. I don’t think we’re going to hold you guys accountable to that. And I will add that you don’t use that many NSAIDs in your patients anyway.

I think those are all great points and we need to do a better job taking that history. That’s just a couple of extra questions separating joint and back pains, asking is it better or worse with rest, and looking at their age. Then on physical exams, actually looking at the joint. Is it swollen and so forth? Let’s say we’re doing this in our office, the patient gets a little worse at rest and is better with exercise. Is this the right time to send them over to you? Should we be doing any other tests in the first place before sending them over to you? Is there a specific time that you think is best?

We’ve collaborated in some studies to try to understand how to screen inflammatory back pain in those kind of patients. I think that for the general practitioner this is a very straightforward and linear imaging test. I’m referring to sacroiliac [SI] joint x-rays, plain x-rays. The reason for that is that that’s very helpful. We’re going to do that no matter what in general. So if you have that patient whom you suspect inflammatory type back pain, you could help us and help the patient accelerate or expedite the workup by doing the x-ray. The reason for that is if we find any images that are representative of sacroiliitis, then we’re done. We say that patient has radiographic axial spondyloarthritis. So we’re done with the assessment.

I understand that it’s hard and you may not want to order the wrong x-ray, but this one in particular is very straightforward. It’s a dedicated sacroiliac joint x-ray. You can’t go wrong with that. Any radiologist would understand that order. Other than that, I think we can do a quick visit and then think about whether or not the next level of imaging studies are necessary, referring to the MRI.

Jose raises a good point about the MRI because our patients with Crohn’s disease in particular get these very often. Many of our radiologists may even comment on the SI joints and we may not be looking. As a gastroenterologist, we don’t really focus on the GI components, but that’s important.

 Jose, maybe you want to comment on this? We had a collaborative publication looking at exactly what Jordan’s saying. Looking at our MR [magnetic resonance] enterographies [MREs] that we have already for Crohn’s disease and actually going back and having our radiologists take a little closer look at the SI joints.

It was a fascinating study. That’s one of those where we made really good use of our collaborations. You guys do MREs. You look at the inflammatory component in the intestinal lumen, but as an add-on, you could look at the sacroiliac joints. It’s in the same area and it’s using MR technology. So we went back and found that somewhere in the order of 20% of the patients you see with Crohn’s disease will have MRIs consistent with sacroiliitis. It is a magnificent way of screening those patients for not necessarily clinically active or symptomatic but yet concomitant axial spondyloarthritis. That’s important because treatment is not necessarily the same, as you were alluding to, Dave. If you have a patient with Crohn’s disease with axial spondyloarthropathy, we have all these new biologic treatments that may or may not affect the spine, for example, or the peripheral joint.

It’s a great point. Now, from this study, our radiologist specifically comments on the SI joints in the report. It was sort of a request we had. Again, there are other tests you can do, but that’s something easy since you already have that information. You’re not spending more time in your office to get that.

Why don’t we pivot to that, Jose, looking at approaches to therapy. Start with psoriatic arthritis. When you’re thinking about treatment options for your patients, what would you go to regularly? Let’s take out IBD for a second and then we could bring that back in. Then, Jordan, let’s hear your thoughts on how we approach it with the concomitant diagnosis.

Great question. Similarly, to the IBD field, psoriatic arthritis patients present in a heterogeneous fashion. It’s not a linear one-size-fits-all therapeutic algorithm. To us it’s very important to understand the intensity or activity of the different domains. It’s not the same to treat someone who has a lot of psoriasis in their skin or someone with a lot of joints with little psoriasis.

I’ll take you through 2 or 3 scenarios. If you have a patient that presents to you with severe active psoriasis and peripheral arthritis, we tend to use a medication or a set of medications that can help both domains. By that, I mean an IL [interleukin]-23 blocker or an IL-17 blocker, because those are superior in some ways to the TNF [tumor necrosis factor] blockers when it comes to psoriasis of the skin. If you have a patient with mostly arthritis and little psoriasis, a TNF is the go-to mechanism for a variety of reasons. It has been for the last decade or decade and a half and would seem to me that it will continue to be the go-to MOA, or mechanism of action, because of the advent of biosimilars. Then we have patients that present, as we were discussing, with axial or spine arthritis. That complicates matters because there are not that many drugs or options. We’re limited to a TNF or an IL-17 blocker. After that we have the JAK [Janus kinase] inhibitors that are being approved for the use in axial or spondyloarthritis. So those are the 3 main scenarios. Purposefully, I didn’t comment on the presence or absence of IBD, but I’m hearing that you have some thoughts on that.

So, Jordan, let’s throw in IBD there with an extraintestinal manifestation, so skin or joint. How are you approaching those patients?

Sure. There’s a couple of really important considerations. What I’ll say is that in IBD we don’t have IL-17 inhibitors. Those have actually been associated with some flares of IBD, so we don’t have them as treatment options. But they are sort of academically interesting for patients who develop GI symptoms on these drugs. That’s almost a separate chat in and of itself.

Similar to what Jose said, a lot of times if there’s axial involvement with inflammatory bowel disease, anti-TNFs tend to be the therapy of choice that seem to benefit both. I think when there’s psoriasis present in psoriatic arthritis, in particular with peripheral arthritis, I think that’s a good indication for the IL-23, IL-12/23 inhibitors. That seems to have pretty good coverage. Now, if a patient has disease severity of their IBD that makes me want to use an anti-TNF or infliximab then I’m still going to use that in that patient, but I think we have some data that suggests IL-12/23 and IL-23s work really well for that patient. Then of course the JAK inhibitors, which are not yet approved in Crohn’s disease but are approved in moderate-to-severe ulcerative colitis, are another option for many of these folks.

The other really important scenario, and Jose it’d be great to get your feedback on this, are for the patients who develop psoriasis while they’re on IBD therapies. This is a different patient in and of itself. So not the patients who come to you treatment naïve with joint pains, new diagnosis of ulcerative colitis, or Crohn’s disease, but the patients who we already have on therapy who now develop a skin manifestation. What are you thinking about?

That’s a great question. It depends on what the background regimen is. We do this all the time at both of our centers. It really is dependent on what the patient has been treated with. In general, that may occur for 2 reasons. One, the medication that’s being used stopped working. Two, something to consider is the paradoxical effects of TNF blockers, for example. We have those patients commonly. It’s not hyper frequent but it’s there. So you have to consider the possibility that some of these patients develop psoriasis secondary to using a TNF blocker. In those scenarios, whether there’s a secondary inadequate response or there’s a paradoxical emergence of psoriasis, we do switch medications or try and think first of using an IL-23 or an IL-12/23 in the absence of axial arthritis. So with peripheral arthritis, for example, or no arthritis at all, but when a patient with IBD on a TNF blocker develops psoriasis we tend to switch to IL-12/23 for obvious reasons. IL-12/23 or IL-23 blockers are exceedingly efficacious in psoriasis. We all know that. And so because they work as well in IBD, then that’s the immediate answer. Could you switch from 1 TNF blocker to the next? Yes, you could. We typically avoid that though. We switch drug classes.

I think it is interesting. Earlier literature for IBD, before we had ustekinumab and risankizumab or IL-12/23, and IL-12 and IL-23, we would switch. Maybe certain TNFs had lower rates of reaction to having another psoriasiform reaction, but it’s still a chance. Jose, briefly comment on how does that psoriasis usually present? Is it differently than a regular psoriasis if it’s from a TNF blocker?

Paradoxical psoriasis more frequently presents as either palmoplantar psoriasis. It’s not infrequent. It could present as plaque or guttate psoriasis, but its the minority of cases. When we get a hint that someone who either never had psoriasis to begin with or had a different type of psoriasis now presenting with palmoplantar lesions, we tend to suspect that that’s paradoxical in nature.

That’s a great point. We are discussing the difference between IL-23 and an IL-12/23. We don’t have great data yet to say that one is necessarily better than the other. They’re equivalent. In rheumatology, do you lean towards one over the other? So would you lean towards an IL-23 inhibitor over ustekinumab, and why?

Unlike the IBD field, we moved away from the IL-12/23. Rheumatologists and the dermatologists as well. It is simply a P19 blocker. A pure IL-23 is simply superior for skin and joints. There’s data for both, more for skin than there is for joints. We actually never used that drug. There’s only one in the market. I don’t think we’ve ever actually used that drug the way you or the dermatologists have. If you ask the company they will tell you that the rheumatologist never went there. And it’s true that the joint response for IL-12/23 is not robust. There are patients that are on it and respond well, but majority won’t. So that’s why we like the P19s now.

Up until recently we only had ustekinumab in our field and now we have risankizumab that obviously brings something different to the table. I guess one of the more challenging things for us, Dave, and it’d be good to get your perspective, is when we have a patient who’s had very severe disease of their IBD and are finally well controlled on maybe a dose-escalated anti-TNF therapy, who now develops a psoriasiform reaction. Is that someone that you think about switching therapies, adding therapies, or what do we do here?

Great point. I would say most of the time the IBD disease burden is more of a significant inflammatory burden than the joint or the skin. If we’re saying that this is a sick patient that failed multiple therapies, maybe had past surgery, or whatever that is, it’s all about efficacy and keeping them in remission. So if I found a therapy that’s working for them and they’re doing well from their IBD perspective, my goal is to keep them on it.

Now, what is the severity of that psoriasiform reaction? Usually if they’re doing well on something, if they could be treated with topical medications or where you could have these mild reactions, I’m keeping them on their TNF. I need to be pushed, and this is my view on a lot of our patients with IBD, especially our more complex patients. If I have them well on something, I really need to be pushed to stop. I’ve had these patients with that exact scenario where they have significant scalp psoriasis and I have to get them off of it, then we’ll talk about it. But in those scenarios, I do whatever I can to stay on the TNFs and then depending on the severity, those are the patients where I think JAK inhibitors are going to play a nice role. We do need some more data on that, but that’s where I think we might lean towards to cover both.

If I may interject, I think it is exactly what you’re saying for the burden of inflammation. We do the same in arthritis. When a patient failed so many other drugs in the past and we finally got them under control, we typically don’t switch that medication at all. The dermatologists, our friends and colleagues, have multiple tricks that they can use. There are topical medications, UV [ultraviolet] light, a little bit of cyclosporine. There’s plenty of things that they can do.

I’m not going to talk about clinical management, but there are clinical trials ongoing where the question is, in patients particularly early in the game, is there a role for combining with the second targeted agent? And again, for the sake of this discussion, this is not clinically available. But a study such as VEGA, which you guys know very well, combining a TNF with an IL-23, or in our case, we have a similar design in the trial that is called AFFINITY. This study is on someone who fails a TNF with the additional IL-23 in psoriatic arthritis. Will it be better than an IL-23 alone to switch to an IL-23? So intriguing times. Those secret patients are important for that particular reason. It may very well be that we get to a combination on those that need it the most.

We’ve had a lot of discussion on combination therapy just in our practices and how we use them, and EIMs I think is a perfect scenario where we are starting to do that by necessity. But I think we need to be more thoughtful in how we use combination therapies. Then something you had just brought up about how we haven’t really seen that benefit in the IL-12/23s for joints. What’s your experience with the selective IL-23 inhibitors with joint symptoms, joint swelling, and so forth?

 It’s a step up compared to an IL-12/23. It really is, the clinical trials show that. Early use compared to a second-line use doesn’t really make a difference. That’s also an advantage. You can use it a second-line and it’s still efficacious. The downside is the spine, as discussed, it doesn’t seem to work on the spine, and therefore we avoid the use of pure IL-23s in those scenarios.

Great. I just want to get your final thoughts on if we’re seeing a patient, when we should refer? If you are seeing a patient, when do you reach out to us? It really sounds like from everything we’re discussing, from IL-17s possibly leading to flares of Crohn’s disease, to side effects of certain medications of our therapies, to the selectivity of our therapies, we should do this before we start. But how does this workflow usually work in your practice?

In general, to me the key here is to have a fluent, fluid, smooth relationship and communication channel open with you guys and the dermatologists. Where you could truly either pick up a phone or send a MyChart note and say, “Here’s a scenario. Can I take 3 minutes of your time? I’ve done fecal calprotectin and it’s borderline. Do you think you want to see this patient, or do you want to wait?” I think that communication is missing in some geographic regions. The more we can do to incorporate those channels of communications to other practices the better for our patients.

Secondly, I think educating on the role of combined care will be very important. Embedded into that is the question of screening. What can we do to help screen for IBD? What can you do in the IBD world to screen for joints? What will we discuss? A third component here is forensic dermatologist, because we have these other EIMs that are so relevant to our patients. By the way, the patients are an N-of-1. They’re their own statistics. So if you only treat the gut, or the joints, or the skin, then we’re losing time, we’re not communicating, and we’re not making anybody any favor.

I think the collaboration is really key and working with the team of course. I think as gastroenterologists it’s important that we recognize our limitations. We’re not dermatologists. We’re not rheumatologists, and so it’s not good enough if patients are really struggling despite being on a therapy that we think is directed for their IBD. If they’re still experiencing active psoriasis or active joint symptoms, then they really need to have expert referral and collaboration to improve care.

I think those are all great points. Early collaboration is key. Finding those people in your area that you could reach out to that you could text or email on thoughts. I think what we could do better as gastroenterologists is just a couple of simple things. Asking those questions about skin, about timing of when these skin or joint symptoms started around medication. Asking that separate question between joint and back pains. Asking about whether that pain is better or worse with rest and exercise. Asking our radiologists to sort of take another look at the MRE at these SI joints. These are very simple things we could do as gastroenterologists that could really help hopefully diagnose or at least take these patients and get them over to rheumatologists so Jose and this team could help out. But I want to thank you, Jose, for joining us. This is a great discussion and we’ll see you soon.

Videos

Dr David Hudesman, Dr Jordan Axelrad, and Dr Jose Scher discuss strategies for managing coexisting inflammatory bowel disease and psoriatic arthritis and highlight the importance of a multidisciplinary approach to providing comprehensive care.

Concurrent Management of Inflammatory Bowel Disease and Psoriatic  Arthritis

To watch the video series component of this episode, click here.

Podcasts

 series titled“Exploring the Evolving Treatment Landscape for Inflammatory Bowel Disease.” I’m Dr David Hudesman, a codirector at the Inflammatory Bowel Disease Center at NYU Langone Health in New York [New York].

I’m Dr Jordan Axelrad, the director of clinical and translation research at the Inflammatory Bowel Disease Center at NYU Langone.

In this program we’ll delve into the long-term management of inflammatory bowel disease and examine the latest treatment options and strategies that can enhance patient outcomes. To discuss more of this, we’re joined by Dr Douglas Wolf, a gastroenterology specialist in Atlanta, Georgia. Thank you so much for joining us. Let’s jump right in.

Dr Wolf, tell us some of the major challenges you have in managing patients with inflammatory bowel disease?

The biggest challenge is the fact that inflammatory bowel disease—both Crohn disease and ulcerative colitis—is a heterogeneous group of disease. There are many forms. For Crohn disease, you can ileo-rectal Crohn, colonic Crohn, fistulizing Crohn, or extra-intestinal manifestations. There are similar challenges with UC [ulcerative colitis]. There are many forms, and we don’t have solid tests to identify which treatment is going to work for an individual patient.

That’s a great point. We all have patients who come in with a friend or a family member who’s had this type of disease or been on this treatment, regardless of whether they’ve done well. We have to explain to them that their disease is personalized. We need to discuss that with them up front before we go into treatments.

Dr Wolf, tell us about how the treatment landscape has changed, especially in recent years, and how that’s influenced your way of approaching patient management and drug selection.

We’re trying to individualize and personalize care for every patient. What’s right for 1 isn’t necessarily right for another. In the past, it was 1 shoe fits all, and patients got a form of mesalamine to start, then prednisone and maybe an immunomodulator. But in the last 10 or 20 years, we’ve had an increasing variety of biologics, which are individually very beneficial. But we don’t know which 1 is going to work for whom. We have many more choices, and we’re learning how to use these options even better. I hope that answers the question.

That’s a great point. The 1 thing I always try to pass along to patients is that whatever the treatment is, what we’ve seen—more with the Crohn data than the ulcerative colitis data, but I believe it’s true for both—is that we want to treat them early. We say, “You’re a patient who’s not doing well now or set up for trouble down the road, so we want to initiate our biologic or small-molecule treatment early.” If we initiate it early, because we don’t have good predictors, which therapy we choose matters a lot less. Unfortunately, we see a lot of patients 2, 5, or 10 years down the road, before they get appropriate treatment.

Jordan, tell us a little about your approach to treatment.Take out the therapy first. What are your goals of therapy? Whatare you discussing with patients?

When I’m seeing a patient in the office, the first thing I do is assess their background disease. You want to know their disease activity and disease prognosis. We use many tools to help us evaluate that with some scoring mechanisms. Obviously, we want to know what their endoscopic activity looks like. That’s included in many of our scores, and it differs. For patients who fit more of severe criteria in ulcerative colitis, I may be thinking about different drugs, anti–TNF [tumor necrosis factor], infliximab [Remicade] in particular. For patients who fit more moderate criteria, I may be thinking of different drugs, anti-integrins like vedolizumab [Entyvio] or even ozanimod [Zeposia]. In Crohn disease, it’s the same thing. With very severe disease activity and prognosis, I’m thinking more about anti-TNF therapies like infliximab. For more moderate disease, I may be thinking about the IL-12/23 and IL-23 drugs, such as risankizumab [Skyrizi] or ustekinumab [Stelara]. Taking in all those considerations, the drug selection has changed.

Doug, what are you telling your patients about the goals of therapy? If you start them on a particular therapy, how are you monitoring them when you’re saying you’re happy or not happy with the response?

It’s very important to follow all these patients closely, so I see patients back in 4 to 8 weeks. And they have rapid access to reach me, so I can get them in earlier if need be. But we want to see that the initial course of therapy, which we call induction therapy, is working. If it’s not, then some of the time, there’s some other explanation that we need to understand and analyze. It could be that there’s a stool infection such as 

] that maybe wasn’t identified or appreciated early. But the bottom line is that we need to individualize these treatments.

With biologics, we sometimes need additional treatment. We sometimes need to use an immunomodulator if we hadn’t initially. Sometimes it’s dosing issues. With the advanced therapies, I’ve seen them work as fast as biologics. At other times, they can take more time. These treatments are agents like ozanimod and upadacitinib [Rinvoq]. They may or may not take a little more time. At least I can see the patient, talk with them, reassure them that we have to give it a little more time, and make sure there’s nothing else going on.

Doug, you mentioned ozanimod and upadacitinib. Tell us a little about how you choose the right patient for those drugs. What are you thinking about and evaluating?

 They’re both great choices. The advantage of ozanimod is that it’s FDA approved for both bio-naïve and bio-experienced patients. If you have a patient who failed on mesalamine and a steroid or something else, give ozanimod a try. It’s very effective. On the other hand, upadacitinib, another very effective treatment, is reserved for patients who have failed anti-TNF therapy in the past.

You mentioned that with ozanimod a lot of data show benefit in that bio-naïve population. When we’re trying to select therapy for a patient, is this the first-line therapy? Last year you presented an abstract at ACG [American College of Gastroenterology Annual Scientific Meeting] looking at a post hoc analysis of True North, the phase 3 trial for ozanimod looking at endoscopic severity. How does endoscopic severity affect you choosing therapy, specifically with ozanimod if that matters?

One great feature that’s well documented with ozanimod is that regardless of baseline disease activity, whether it’s moderate or severe, and baseline endoscopic activity, whether it’s moderate or severe, ozanimod’s efficacy is well demonstrated by significant reductions in calprotectin levels and other measures. It works well for bio-naïve and bio-experienced patients, those in the moderate realm and those in the severe disease activity realm. It covers a broad range of patients.

What’s important about that is this new class of small molecules is oral. This is a new area. How we can take care of patients without injectables or infusions? This offers an opportunity to provide a mode of administration that we haven’t had in recent years, which is important.

That’s how I’m using it in my practice. If I have a patient on that moderate-to-severe ulcerative colitis spectrum—the more moderate end is bio-naïve—that’s where the strength of the ozanimod data is. If there’s failure of 1 biologic, there are some good data there as well. Once you get to multiple biologic failures—I don’t usually go to this as the next step—that’s where it fits in nicely. It has worked well, whether they have a Mayo Score of 2 or 3, meaning moderate inflammation on colonoscopy or ulceration. Then we have that discussion: efficacy, safety, is the patient traveling a lot? Do they have to come in for an infusion or injection? Having that oral option is important. Talk a little about safety of ozanimod and your thoughts about the safety profile or anything that concerns you.

There really isn’t. It’s a relatively safe agent in the context of the other agents we have to offer. There’s some initial testing done, as with other agents. It includes some cardiac monitoring done initially. Ozanimod doesn’t cause any cardiac issue. It’s a matter of being sure that everything lines up. Basically, it’s some blood work. The safety has ended up being very favorable. I’m very comfortable offering it to an array of patients with ulcerative colitis.

It’s important to keep in mind with ozanimod that patients with cardiac conduction abnormalities are the ones you have to be careful of. Check their baseline ECG [electrocardiogram], and make sure they’re candidates for therapy. Although in inflammatory bowel disease, because many of our patients are younger, they don’t have as many cardiac comorbidities, so that’s not an issue. We don’t have as much data using this agent in women who become pregnant.

The only other thing I’ll add is that the lymphocyte count in half the patients will drop, but that’s expected. It plateaus after a couple of months on treatment and stays that way. That drop in lymphocyte count—we expect that with thiopurines—hasn’t been associated with any severe or serious infections. It’s something to be aware, but not something to be nervous about.

Exactly. I’ll add that we’ve published on that. Although some relative lymphopenia occurs, it’s not associated with any untoward events. There’s still a sufficient number of lymphocytes circulating despite the mechanism of action to protect us. We should feel comfortable with that.

For moderate to severe ulcerative colitis—the way I look at it, more on the moderate end—we have vedolizumab, ustekinumab is a good option, ozanimod. We talk about this because of good efficacy with a nice safety profile. Doug, what about upadacitinib? It’s 1 of the other new oral small molecules that the FDA recently approved for moderate to severe ulcerative colitis. Talk a little about that agent and how you’re incorporating it into your practice.

Upadacitinib is a JAK inhibitor. Because it’s in that class, a patient has to have failed an anti-TNF before utilizing it. But if the patient is ready for the next step after going through an anti-TNF, upadacitinib is an excellent option. Similar to Zeposia [ozanimod] in a way, it can be an excellent alternative to biologic therapy. Both options can be used even in patients who failed 1 or 2 biologics. I’ve seen them work. It’s a different mechanism. As with many other agents, when we try them as a second or third choice, they don’t work quite as well as if we had used them as a first choice. The data suggest that, but they still work. That’s where it's appropriate to reassure our patients that it may take a little longer to work. But getting back specifically to upadacitinib, it’s an excellent choice with activity. Its effectiveness is similar to what we’ve seen in biologics.

We mentioned the adverse effect profile and some of the monitoring that has occurred before initiating ozanimod. Is there anything you’re doing with upadacitinib in particular or the JAK inhibitor class more generally?

No, and you may be able to address the specifics a little better. But there are class cautions. There are patients who have cardiac disease and cardiac morbidity. Those are individuals with whom we’d be more cautious about using upadacitinib. But the vast majority of patients with IBD [inflammatory bowel disease] don’t fit in that category, and so it’s an excellent option.

I agree. It’s similar to the ozanimod risk profile. A lot of our patients don’t have a lot of cardiac comorbidities. Some of the big ones with upadacitinib are the risk of venous thromboembolism: PE [pulmonary embolism] and DVT [deep vein thrombosis] . Those have popped up in some of the post hoc analyses of use of tofacitinib [Xeljanz], which is another JAK inhibitor and an oral small molecule for moderate to severe ulcerative colitis. Also there are some infection risks—Zoster, the shingles—that we’re identifying as well. But our patients would be lower risk.

That data have come out, and many of us are well aware from a rheumatology study that these are older patients. When we look at this class in our patients with ulcerative colitis, young and old, we haven’t seen that. We still need longer-term follow-up. It’s something to be aware of and discuss, but it’s not a reason not to use a therapy. Jordan, what has your experience been? What type of patients are you using upadacitinib in?

This is reserved for patients who are anti-TNF refractory. In general, these patients are going to be a much sicker patient, more severe on the moderate-to-severe spectrum. That’s who we’re using the drug in. These are infliximab, IV [intravenous], anti-TNF failures. The benefit of a drug like upadacitinib, as with most oral small molecules, is that it also tells you whether it’s going to work very quickly. If patients are going to respond to drug, they usually start to feel better early on in the treatment during the induction period, which is important. But I reserve this for sick patients who have failed other biologics.

I have 1 more comment on this. I agree completely. When I’m looking at the moderate-to-severe spectrum for ulcerative colitis, moderate is vedolizumab, ustekinumab, and ozanimod. Severe doesn’t mean hospitalization, but we’re talking infliximab and upadacitinib. I’ve seen very good results. There have been some nice post hoc analyses showing that within a couple of weeks, over 60% of patients don’t have any more rectal bleeding. When we’re talking about goals of care, we want the calprotectin to drop. We want the CRP to drop. But we have the patients. We want them to feel better quickly. Those agents work very quickly.

One of the lingering questions we’re encountering and learning from is how we can sequence some of these drugs—vedolizumab, then ozanimod—in that patient. What do you think about that moderate who’s failed a biologic? Would you be thinking about a different agent there?

Yes, I think so. That’s a great question. I still look at severity when approaching positioning or sequencing on the severity. I like to go to what’s worked in the past because we don’t have…very good predictors of response for our therapies. If a patient has done well on vedolizumab for years and then lost response, and it’s unclear why that happened, ozanimod would be a good option. It has a similar mechanism and anti-trafficking. Why wouldn’t that work? On the same note, if a patient has done well with an anti-TNF for a while, we can pivot to another therapy. But you know they do respond to that drug class. If they develop antibodies and lose response, it makes sense to go to that same class where we know something works. It’s nice that we have these options, but it brings up important sequencing questions.

The immune system is very complicated. It’s difficult to predict the right sequencing. I have a few patients who were primary failures with vedolizumab and then went into remission on ozanimod. It’s hard to predict. The bottom line is that we don’t have true predictors…. We’re fortunate that we have more class options to try in this difficult disease.

That’s a great point. Let’s pivot to Crohn disease. We have ozanimod and upadacitinib as new or small molecules for ulcerative colitis. For Crohn disease, our newest agent is risankizumab, a selective IL-23 inhibitor. Doug, maybe you could touch on the data, how you’re using this agent in your practice, and how you’re incorporating it in your sequencing.

Risankizumab is a great option when a biologic is needed for Crohn disease. It’s more selective than the IL-12/23 agents. That may lead to an advantage. I don’t think we know at this point. But this agent is very well tolerated. The 3 IV infusions that are used to provide induction therapy are incredibly effective at providing a response and a remission by the end of induction. The IV induction and subcutaneous maintenance strategy that’s been designed for this agent is excellent and a great option.

Dave, tell us how you’re choosing the right sequencing of therapies in Crohn disease and how you’d manage a moderate vs severe patient differently.

With risankizumab, I agree with everything Doug showed. There are some nice efficacy data showing the difference between drug and placebo, which we haven’t seen as much in other patients with Crohn disease. Once you’re first vs second vs third line, a lot of times we see that dip, but with risankizumab there’s still a persistent difference between drug and placebo when you go first, second, or third line. It’s a very effective agent. How do I position it along that moderate-to-severe spectrum? In more moderate patients, before risankizumab, I used a lot more ustekinumab in the first line. I’m starting to transition that to risankizumab. It hasn’t been on the market for long, so I need some more real-world experience. I’ve been using that more as the first-line agent, but in uncomplicated Crohn, I’ve seen efficacy in the second line. With Crohn, if there’s anything that concerns me—significant small bowel disease, significant deep ileal ulceration, perianal disease—I stick with anti-TNF. I’m still using a good amount of anti-TNF in the first, second, and third lines, mostly infliximab and adalimumab. I’m seeing risankizumab used more in Crohn, but if anything concerns me, I lean on the anti-TNF.

Doug, how you think about patients who are refractory to ustekinumab? Is that a patient for whom you’d consider risankizumab after? How are you evaluating that?

Good question. I’ve used risankizumab in the bio-naïve and the multibiologic failure Crohn populations, including those who’ve apparently lost response to ustekinumab. There have been benefits. That’s been seen in the clinical trials, and I’ve seen it in clinical practice. It’s different enough from all the others that it’s a go-to agent when you need it for what one might term as salvage or simply another option. It’s effective.

You brought up an interesting point about the comparison between ustekinumab and risankizumab, and we’ll have further head-to-head studies. We don’t have them yet for IBD, but if you look at psoriasis, the selective IL-23 inhibitor outperformed ustekinumab. There are some phase 2 data, with a different IL-23 inhibitor guselkumab [Tremfya] looking at ulcerative colitis. Maybe there was a trend toward better healing. This is something that will be interesting in terms of efficacy. Is there a difference? We don’t know, but this is another very safe agent, and we’re comfortable with that.

The class of IL-23 inhibitors is going to be a growing class in our field, as it has been in other immune-mediated disease states.

Let’s pivot to something that’s going to impact all our practices and will probably be a headache: biosimilars, biosimilar adalimumab [Humira], and others coming to market. What are your thoughts on biosimilars? Does anything concern you about the use of them? Right now we have infliximab and adalimumab biosimilars.

Biosimilars do add an option for treatment. It’s not a class alternative. If one hasn’t benefited from the reference or originator agent, one isn’t likely going to benefit from the biosimilar. The reason they’re out there and that the government has backed this is the hope that it will bring down prices of biologic anti-TNF and other agents as they come out. Whether this is true, I’m not sure. I don’t know if it reduces cost for patients, but that’s a consideration. They don’t have the same access systems to provide free drugs to indigent patients, but that’s an alternative. Insurance companies have basically mandated switches to biosimilars. The challenge with an infliximab is that 1 year a patient switches to 1 biosimilar, and then another year they may be switched to another. No facility, whether it’s a hospital or a practice, can stock more than 1 or 2 of these agents. In the past we were able to manage and monitor these patients well in our infusion units. Now we need to farm them out to sites that can give a particular biosimilar agent. That wasn’t anticipated, but it’s a challenge to all our practices.

The new learning curve with adalimumab biosimilars is that there are going to be many new devices. Our patients, our staff, and we are going to have to be familiar with multiple different devices and how they should be utilized and stored. It’s going to be a steep learning curve, especially because adalimumab is able to be swapped out at the pharmacy. We may not know if patients are getting an originator vs a biosimilar that their individual policy covers.

It’s important that we learn from one another about how to incorporate this into our practice. That’s exactly my biggest concern. There have been multiple studies—infliximab, adalimumab, different disease states. I’m not worried about efficacy or safety or drug levels, antibodies, or anything like that. How do you use it in practice? Is the patient aware? We’ve learned from this that when we used infliximab, the patient came to an infusion center, and sometimes they found out that day that they were getting the biosimilar before they heard from us when it first came out. That’s not the way you want to do that. There’s a lot of concern and anxiety, and the key is education, having the staff communicate with the patients, letting them know ahead of time, determining the right workflow. For me, that’s the biggest concern.

We’ve had a great discussion about how we’re positioning therapy, how we’re sequencing therapy, and how we’re incorporating some of our newer agents. Maybe we could go around and ask each of you what you’re most excited about in the next couple of years, whether that’s newer therapies or different uses of our current therapies. Doug, let’s start with you.

There are 2 areas. One is whether monotherapy with anti-TNF and infliximab is best, or whether it’s a combination therapy. I use monotherapy the most because I’ve seen the most severe complications, primarily lymphoma associated with combination therapy and immunomodulators, especially 6-MP [6-mercaptopurine] and azathioprine [Imuran]. We’re still sorting that out. The other topic is combination biologics. I’ve been involved in a couple of clinical trials that used them with efficacy and safety. That may be the better way to add a second agent in the moderate or severe disease severity category, when you really need the best combination for your patients. The challenge is getting an insurer to pay for it. We’ve been successful selectively in using it, but the majority of cases have resulted in denial. I don’t know how things have worked in your facility.

Doug, you alluded to part of it. These combination biologic studies are very intriguing, especially for our sick, complicated patients. What we’ve learned from some of those studies, particularly in Crohn disease, is that arms that included an IL-23 agent, even a monotherapy, was effective. I look forward to moving forward better utilization of different IL-23 agents and how that class may help our patients. Combination therapy looks better, but how that can be done is a question.

Expert gastroenterologists delve into the long-term management of Crohn’s disease and ulcerative colitis and examine the latest treatment options and strategies to enhance patient outcomes.

Jordan Axelrad, MD, MPH

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